The maior goal of this proposal is to understand the role of a signaling adapter molecule TRAF6 in the regulation of T cell fates. T cell fates and immune responses are controlled by multiple factors including antigen receptors, costimulatory molecules, and microenvironmental cytokines. This application stems from our studies on the physiological role of TRAF6 in vivo. TRAF6 is a major signaling molecule for immunoreceptors such as the TNF receptor family members RANK or CD40, and IL-1/Toll-like receptors (TLR) that are shown to be critical mostly for the control of proper innate immune responses. To date, therefore, the role of TRAF6 in regulating T cell proliferation, survival, and immune homeostasis in vivo per se has not been examined in detail. Our preliminary data, generated from TRAF6 -/-mice, chimeras using hematopoietic cells from TRAF6 -/- mice, and TRAF6 -/- mice created by RAG-2 -/- blastocyst complementation show that T cells from all these mice have an elevated number of activated cells (by phenotype), defective proliferative responses, and when examined, accelerated cell death. Studies in the chimeras show an autoimmune-like syndrome with T cell hyperproliferation, further suggesting a role for TRAF6 in regulating autoimmunity. These results are unexpected and surprising since TRAF6 utilizing immunoreceptors are mostly implicated in regulation of APC function. Therefore, we propose to extend the study of T cell biology regulated by TRAF6 by pursuing the following two major aims. The first goal is to determine the role of T cell-expressed TRAF6 in lymphoid development and function by utilizing conditional TRAF6 knockout mouse generated in our laboratory and described in the preliminary data section. The second is to determine the defects in the T cell arm contributing to autoimmunity observed in the TRAF6 deficient mice. The proposed studies should provide previously unappreciated molecular and cellular control of T cell fates in vivo. These will, in turn, provide the basis for design of new immunotherapeutic strategies against tumors, viral diseases, or autoimmune diseases that may arise from inadequate or inappropriate immune responses.